WO2018165132A1 - Polyphosphates à titre d'inhibiteurs de cristallisation du calcium - Google Patents

Polyphosphates à titre d'inhibiteurs de cristallisation du calcium Download PDF

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Publication number
WO2018165132A1
WO2018165132A1 PCT/US2018/021108 US2018021108W WO2018165132A1 WO 2018165132 A1 WO2018165132 A1 WO 2018165132A1 US 2018021108 W US2018021108 W US 2018021108W WO 2018165132 A1 WO2018165132 A1 WO 2018165132A1
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Prior art keywords
groups
composition
patient
polyphosphate
pathological calcification
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Inventor
Jeffrey D. Rimer
Bryan G. ALAMANI
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University of Houston System
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University of Houston System
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis

Definitions

  • This disclosure relates generally to inhibiting mineral crystallization.
  • Kidney stones are one example of pathological calcification. Crystalized calcium oxalate is a common constituent of many types of kidney stones and it is thus considered that saturation (attendant to crystallization) of calcium oxalate compounds within the kidneys is likely a precondition to the formation of these types of kidney stones. While calcium oxalate stones are a common type of kidney stone, calcium phosphate (such as brushite) stones are also prevalent.
  • kidney stones While various treatments for kidney stones exist and may be effective, they do not always prevent post-treatment reoccurrence of kidney stones. Some existing kidney stone treatments are physically invasive and thus carry significant risks to the patient. Drug-based treatments relying on compounds such as hydrochlorothiazide, sodium phosphate, and potassium citrate are available, but effectiveness (and side effects) may vary patient-to-patient. Some compounds, such as citrate and hydroxycitrate, which act to dissolve calcium oxalate crystals that have formed within the body, are known, but new treatments for pathological calcification could be beneficial to some patients.
  • compounds such as citrate and hydroxycitrate, which act to dissolve calcium oxalate crystals that have formed within the body, are known, but new treatments for pathological calcification could be beneficial to some patients.
  • a composition for inhibiting pathological calcification comprises a polyphosphate material and a pharmaceutically acceptable carrier.
  • Polyphosphate material may be a polyphosphate, a polyphosphate derivate, or combinations including a polyphosphate and a polyphosphate derivative.
  • a method of treating pathological calcification comprises administering a composition to a patient, the composition including a polyphosphate material and a pharmaceutically acceptable carrier. In some examples, the composition may be administered in a therapeutically effective amount to the patient.
  • Pathological calcification includes, without limitation, abnormal biomineralization associated with kidney stones, hypercalciuria, gout, and atherosclerosis.
  • a method of controlling pathological calcification in a patient comprises administering a composition including at least one of a linear tripolyphosphate material and a hexametaphosphate material.
  • a linear tripolyphosphate material may be a linear tripolyphosphate, a derivative of linear tripolyphosphate, or combinations including a linear tripolyphosphate and a derivative of linear tripolyphosphate.
  • a hexametaphosphate material may be a hexametaphosphate, a derivative of hexametaphosphate, or combinations including a hexametaphosphate and a derivative of hexametaphosphate.
  • FIG. 1 A depicts a linear polyphosphate
  • FIG. 1 B depicts a functionalized/derivative form of a linear polyphosphate.
  • FIG. 1 C depicts a hexametaphosphate.
  • FIG. 1 D depicts a functionalized/derivative form of a hexametaphosphate.
  • FIG. 1 E depicts a branched polyphosphate
  • FIG. 1 F depicts a functionalized/derivative form of a branched polyphosphate.
  • FIG. 1 G depicts a functionalized/derivative form of a linear polyphosphate.
  • FIG. 2A depicts a non-exhaustive collection of possible functional groups that can be used as or incorporated into "Ft" groups on various polyphosphate materials in accordance with preferred embodiments described herein.
  • FIG. 2B depicts additional exemplary functional groups that can be used as or incorporated into "Ft" groups on various polyphosphate materials in accordance with preferred embodiments described herein.
  • FIG. 2C depicts additional exemplary functional groups that can be used as or incorporated into "R" groups on various polyphosphate materials in accordance with preferred embodiments described herein.
  • FIG. 3 depicts experimental results obtained using various polyphosphate materials to inhibit crystallization of calcium oxalate from aqueous solution.
  • FIG. 4A depicts optical microscope images showing results of calcium oxalate crystallization from a control solution and solutions including a linear polyphosphate material NasPaC o at concentrations of 5 ⁇ and 15 ⁇ .
  • FIG. 4B depicts effects of NasPaCho concentrations on calcium oxalate crystal frequency.
  • FIG. 5A depicts optical microscope images showing results of calcium oxalate crystallization from a control solution and solutions including a cyclic polyphosphate material (NaPC>3)6 at concentrations of 0.3 ⁇ and 0.7 ⁇ .
  • FIG. 5B depicts effects of (NaPC>3)6 concentrations on calcium oxalate crystal frequency.
  • FIG. 6 depicts optical microscope images showing changes in crystal habit for calcium oxalate crystals in a control solution and solutions including a linear polyphosphate material NasPsCho at concentrations of 5 ⁇ and 15 ⁇ .
  • This disclosure is related to new compounds and methods utilizing these new compounds that may act to reduce the incidence and/or reoccurrence of kidney stones and/or other pathological calcification symptoms or conditions.
  • polyphosphate materials are described herein as inhibitors of calcium oxalate crystal nucleation and growth. More generally, disclosed polyphosphate materials can be used to slow the rate of calcium mineral growth.
  • examples of calcium minerals include, without limitation, calcium oxalate, calcium phosphate, and calcium carbonate.
  • Disclosed polyphosphate materials include polyphosphates and polyphosphate derivatives that can be used in therapeutic treatments to prevent or slow the incidence of the formation of minerals (biomineralization) which can occur in a patient with various diseases or conditions, for example, without limitation, kidney stones, hypercalciuria, atherosclerosis (calcified plaque), and gout.
  • a "patient” is understood to encompass all mammals including humans.
  • “Therapy” and “therapeutic treatment,” as used herein, encompass administering a compound to a patient for the purposes of curing a disease condition, ameliorating a disease condition, preventing a particular symptom of a disease condition, ameliorating a particular symptom of a disease condition, reducing the risk of the incidence or recurrence of a disease condition, or reducing the incidence, recurrence, or severity of a particular symptom of a disease condition.
  • Polyphosphate materials can be used in combination with other compounds for combination therapies to cure, ameliorate, or prevent conditions, symptoms, or diseases related to pathological calcification.
  • the phosphate materials may be mixed with or into a pharmaceutically acceptable carrier. Acceptable carriers depend on intended route of administration.
  • the administered composition may also include other active ingredients, adjuvants, and/or excipients.
  • Polyphosphates are rich in negatively charged functional groups that interact with free calcium (Ca 2+ ) ions in solution (via complexation) and/or with calcium at the surface of crystals (such as calcium oxalate monohydrate).
  • the interaction between polyphosphate and calcium materials may function to inhibit calcium-compound crystallization.
  • Polyphosphates are anionic molecules consisting of multiple phosphate functional groups. In physiological environments (e.g., in vivo), the phosphate functional groups can exhibit a range of disassociated states according to the acid/base chemistry of the environment and the disassociation constants (pKa values) of the functional groups in the molecule. Polyphosphates molecules are generally water soluble. In an aqueous environment, the polyphosphate molecules can complex with other species in solution, such as ions, small molecules with ionic character, or larger molecules having at least portions with ionic character. In solid state, polyphosphates may be present as salts.
  • Polyphosphates can be conceptually grouped in to three different categories according to basic structure types: linear polyphosphates, cyclic polyphosphates (also referred to as “metaphosphates"), and branched polyphosphates (also referred to as "ultra-phosphates").
  • Linear polyphosphates include three or more phosphate groups connected in series.
  • Cyclic phosphates include three or more phosphate groups connected in a ring structure.
  • Branched phosphates include four or more phosphate groups or those in which at least three groups are directly attached to the fourth group.
  • the biocompatibility and/or aqueous solubility may eventually decrease for very large molecules.
  • FIGs. 1 A-1 G depict structures of various types of polyphosphate materials.
  • FIG. 1 A depicts a linear polyphosphate and
  • FIG. 1 B depicts a functionalized/derivative form of the linear phosphate including "Ft" groups.
  • FIG. 1 C depicts a hexametaphosphate and
  • FIG. 1 D depicts a functionalized/derivative form of a hexametaphosphate with "Ft" groups.
  • FIG. 1 E depicts a branched polyphosphate and
  • FIG. 1 F depicts a functionalized/derivative form of a branched polyphosphate, with "Ft” groups.
  • Branched polyphosphate may also be referred to as "ultraphosphate.”
  • FIG. 1 G depicts a functionalized/derivative form of a linear polyphosphate including an "Ft" group in the backbone.
  • the "Ft" groups that can be used to derivatize or functionalize the polyphosphate materials of the present disclosure can be any suitable substituent group.
  • Each "Ft” group may be different from the other "Ft” groups in the same compound. That is, conceptually at least, each "Ft” group depicted in the functionalized/derivative forms may be independently selected even though, in practice, synthetic compatibility and site selectivity may have to be considered in selecting different "Ft" groups within the same molecule.
  • acyl groups alkyl groups, cycloalkyl groups, cycloheteroalkyi groups, aryl groups, arylalkyi groups, acylamino groups, acyloxy groups, alkoxy groups, alkoxycarbonylamino groups, substituted alkenyl groups, alkenyl groups, alkylene groups, alkenylene groups, alkynyl groups, alkanoyl groups, fused aryl groups, alkaryl groups, arylamino groups, alkoxyamino groups, alkoxycarbonyl groups, alkylarylamino groups, alkylsulfinyl groups, alkylthio groups, amino groups, aminocarbonyl groups, aminocarbonylamino groups, arylalkyloxy groups, aryloxycarbonyl groups, arylsulf
  • FIG. 2A depicts several possible functional groups that can be used as and/or incorporated in "Ft” groups on polyphosphates described herein in accordance with preferred embodiments, including those in FIGs. 1 B, 1 D, 1 F, and 1 G.
  • FIG. 2A is not an exhaustive listing of possible functional groups.
  • "n” indicates a repeating unit
  • "x” indicates a heteroatom (i.e., not carbon)
  • “Ft and "R2" are additional suitable functional groups.
  • “Ri” and “R2” may be independently selected when multiple “Ri” or “R2" groups are present in a depicted group in FIG. 2A.
  • FIG. 2B shows exemplary "R” groups having "R1 " substituents
  • FIG. 1 shows exemplary "R1 " substituents
  • FIG. 2C shows additional exemplary forms of "R" groups in which Ri may be OH or CH3.
  • Ri may be OH or CH3.
  • FIG. 1 G it is noted that the "R” group is in the main backbone of the phosphate material and thus the "R” group must have two bonds, which are not depicted in FIG. 2A-2C. Suitable adjustments to the "R” groups illustrated in FIG. 2A-2C can be made to address this, such as by using Ri or R2 groups that are CH2 rather than CH3.
  • This disclosure includes these various polyphosphates and polyphosphate derivatives and their corresponding salts, solvates, co-crystals, prodrugs, isomers, tautomers, and isotopic variants.
  • these materials may be prepared as salts with corresponding cations, such as sodium or potassium or other alkali metals, or in solvated form in which surrounding solvent molecules compensate for the anionic character of the polyphosphate materials.
  • LTPP linear tripolyphosphate
  • n is 1 or more, in certain preferred embodiments n is between 1 and 8, and in additional preferred embodiments n is 1 .
  • Additional preferred embodiments include the salt form of the LTPP, such as NasPaCho.
  • a LTPP in accordance with preferred embodiments may have the following structure:
  • n is 1 or more, in certain preferred embodiments n is between 1 and 20, and in additional preferred embodiments n is 1 .
  • the R groups may independently be any suitable R group identified above or in FIGs. 2A-2C.
  • R is independently selected from acyl, alkyl, acyloxy, and alkoxy groups.
  • HMP hexametaphosphate
  • Additional preferred embodiments include the salt form of the HMP, such as
  • HMP hexametaphosphate
  • R groups may independently be any suitable R group identified above or in FIGs. 2A-2C.
  • R is independently selected from carbonyl groups such as carboxylic acids.
  • a LTPP in accordance with preferred embodiments may have the following structure:
  • n 1 or more, in certain preferred embodiments n is between 1 and 20, and in additional preferred embodiments n is 4.
  • the R groups may independently be any suitable R group identified above or in FIGs. 2A-2C, with accommodations made to address the need for two bonds to the main backbone of the structure.
  • R is independently selected from acyl, alkyl, acyloxy, and alkoxy groups.
  • a branched polyphosphate in accordance with preferred embodiments may have the following structure:
  • a branched polyphosphate in accordance with preferred embodiments may have the following structure:
  • R groups may independently be any suitable R group identified above or in FIGs. 2A-2C.
  • R is independently selected from acyl, alkyl, acyloxy, and alkoxy groups.
  • Disclosed polyphosphate materials may be administered to a patient by any known mechanism for drug delivery, such as, without limitation, oral, transdermal, and/or intravenous. Administration to the patient may be enteral or parenteral.
  • the polyphosphate materials may be included in, for example, capsules, tablets, pills, powders, or grains. These formulations may include, for example, starch, sucrose, lactose, talc, gelatin, sodium alginate, and polyvinyl alcohol.
  • the polyphosphate materials may be included in, for example, syrups, elixirs, oil-in-water emulsions, water-in-oil emulsions, aqueous solutions, non- aqueous solutions, aqueous suspensions, or non-aqueous suspensions.
  • the polyphosphate materials may be included in creams, gels, and ointments.
  • the polyphosphate materials maybe formulated for extended release.
  • Pharmaceutically acceptable carriers are materials that permit or allow the active ingredient(s) of a composition to be administered to a patient by at least one acceptable route.
  • the active ingredient would include polyphosphate materials.
  • the pharmaceutically acceptable carrier is preferably safe for patient intake and compatible with the active ingredient.
  • the carrier may be a solid, a liquid, or a gas at an expected temperature for administration and/or storage, for example, approximately room temperature (25 °C).
  • the administered composition including the polyphosphate material may further include other active compounds intended to dissolve calcium oxalate crystals, inhibit calcium oxalate crystallization, or complex calcium ions. Buffers, diluents, stabilizers, flavorings, emulsifiers, suspending agents, binders, preservatives, and/or thickening agents and the like may also be incorporated when considered desirable or necessary. Routes of administration include, but are not limited to oral, dermal, inhalation, injection, and intravenous.
  • FIG. 3 depicts experimental results obtained using an example of a LTPP compound (NasPaOio) and an example of a HMP compound ((NaPC>3)6) to inhibit crystallization of calcium monohydrate (COM) from aqueous solution.
  • Results for a citrate compound (NaaCeHsG/) which is commonly used in the treatment of kidney stones, is presented for purposes of comparison.
  • the x-axis represents a measure of concentration (micromolar ( ⁇ ) concentration on a logarithmic scale) of the inhibitor present in the solution.
  • the y-axis represents percent inhibition (% reduction in the rate of crystallization) of COM crystallization as compared to a control solution having no inhibitor compounds therein.
  • ISE ion selective electrode
  • the % inhibition refers to the averages of at least 3 separate experiments.
  • the solutions tested were aqueous solutions of calcium chloride (CaC ), sodium oxalate (Na2C20 4 ), and sodium chloride (NaCI).
  • the tested solutions further included the inhibitor/modifier compound at the stated concentration level.
  • the HMP compound demonstrated approximately 100% inhibition at lower inhibitor concentrations than the other compounds depicted, including citrate, the current leading therapy.
  • the HMP compound achieved approximately 100% inhibition at a concentration of less than about 1 ⁇ .
  • the LTPP compound demonstrated inhibition of 30-1 00% in a concentration range of about 5 ⁇ to about 125 ⁇ .
  • the citrate compound appears to inhibit crystallization only up to about 60% even when much higher solution concentrations are used.
  • FIG. 3 shows the citrate compound achieves only about 60% inhibition at a concentration of around 320 ⁇ .
  • FIG. 4A depicts optical microscope images showing results of calcium oxalate crystallization from a control solution and solutions including LTPP NasPaOio at concentrations of 5 ⁇ and 15 ⁇ .
  • FIG. 4B depicts effects of NasPaCho concentrations on calcium oxalate crystal frequency. Only very small crystals were observed as being formed from the LTPP containing solution at the 15 ⁇ concentration level. Crystals formed from the control solution were approximately 25-50 ⁇ in size as measured along the c-axis, which is the longest dimension. As shown in FIG. 4B, higher LTPP solution concentrations resulted in no definitive crystals being observed.
  • FIG. 5A depicts optical microscope images showing results of calcium oxalate crystallization from a control solution and solutions including HMP (NaPC>3)6 at concentrations of 0.3 ⁇ and 0.7 ⁇ .
  • FIG. 5B depicts effects of (NaPC>3)6 concentrations on calcium oxalate crystal frequency. Very small crystals were observed as being formed from the HMP containing solution at the 0.7 ⁇ concentration level. Crystals formed from the control solution were approximately 25-50 ⁇ in size as measured along the c-axis, which is the longest dimension. As shown in FIG. 5B, higher HMP solution concentrations resulted in no definitive crystals being observed.
  • FIG. 6 depicts optical microscope images showing results of calcium oxalate crystallization during bulk studies at different concentrations of LTPP.
  • the leftmost image is a representative control crystal.
  • the middle image shows a crystal prepared with 5 ⁇ LTPP.
  • the rightmost image shows a crystal prepared with 1 5 ⁇ LTPP.
  • crystal growth inhibition may occur through molecule adsorption onto the growing crystal surface.
  • the molecule may block or impede additional crystal material adding to existing surface(s) of the crystal.
  • a polyphosphate (or a polyphosphate derivate) may include a number of possible sites available to adhere to the crystal surface.
  • crystal growth may be hinder by polyphosphate molecules which act to at least temporarily bind or otherwise interact with free cations (e.g., Ca 2+ ) in solution.
  • polyphosphate materials that include derivatives or functionalized forms of the LTPP and HMP compounds tested herein would demonstrate similar or even improved effects because they would have enhanced interactions with the crystal material. It is further expected that LTPP compounds having a longer backbone than the LTPP compound tested herein would demonstrate similar or even improved effects because of the availability of multiple binding groups interacting with the crystal material.

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Abstract

De manière générale, les modes de réalisation ci-décrits concernent des compositions et des méthodes nécessitant ces compositions qui peuvent agir pour réduire l'incidence et/ou la réapparition de calculs rénaux et/ou autres maladies, symptômes ou affections de type calcification pathologique. Les compositions comprennent un matériau de polyphosphate, qui peut être un polyphosphate ou un dérivé de polyphosphate. Dans certains modes de réalisation, les compositions comprennent en outre un véhicule pharmaceutiquement acceptable. Les compositions peuvent être administrées à un patient à titre, par exemple, de méthode de traitement de calcification pathologique. Dans certains modes de réalisation, le matériau de polyphosphate contenu dans la composition à administrer peut être un matériau de tripolyphosphate linéaire ou un matériau d'hexamétaphosphate.
PCT/US2018/021108 2017-03-06 2018-03-06 Polyphosphates à titre d'inhibiteurs de cristallisation du calcium Ceased WO2018165132A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN115475156A (zh) * 2022-09-15 2022-12-16 广州医科大学附属第一医院（广州呼吸中心） 羟基柠檬酸在制备防治兰德尔斑药物中的应用

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WO1996039115A1 (fr) * 1995-06-06 1996-12-12 Indiana University Foundation Procede et composition contre le tartre dentaire chez les animaux domestiques
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US3281322A (en) * 1961-09-11 1966-10-25 Ashmead Harvey Methods for controlling and treating renal calculi
GB1132233A (en) * 1965-10-22 1968-10-30 Harvey Ashmead Medicinal compositions containing sequestering and chelating agents
WO1996039115A1 (fr) * 1995-06-06 1996-12-12 Indiana University Foundation Procede et composition contre le tartre dentaire chez les animaux domestiques
WO2005044189A2 (fr) * 2003-10-28 2005-05-19 Emory University Dialysats et procedes et systemes correspondants
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C.W.VERMEULEN ET AL.: "Prevention of Phosphate Stones by Phytate, Phosphate and Hexametaphosphate: Experimental Urolithiasis XV", vol. 82, no. 2, August 1959 (1959-08-01), pages 249 - 255, XP002781267, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S0022534717658713?via%3Dihub> [retrieved on 20180523] *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115475156A (zh) * 2022-09-15 2022-12-16 广州医科大学附属第一医院（广州呼吸中心） 羟基柠檬酸在制备防治兰德尔斑药物中的应用

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